Objective: One goal is to determine how two important and distinct brain pathways are changed as a result of Parkinson’s disease (PD). The pathways involve brain regions called the thalamus and the striatum. The second goal is to determine whether these pathways be made to behave normally with specialized drugs, and whether this alleviates motor symptoms in mice that have PD symptoms.

Background: It has long been known that changes in the striatum from PD are as a result of dopamine neuron loss in the substantia nigra (SN) and contributes to the motor symptoms of PD. However, the striatum also receives inputs from another other brain region, the thalamus. Early in PD, this brain region will also exhibit Lewy pathology, but little is known about how the thalamus pathways change over the course of PD. We hypothesize that changes in the thalamus may contribute to the imbalance between brain pathways that is seen in PD, resulting in slowed movement. Recent advances in the field of neuroscience has allowed us to control particular populations of neurons using light and specialized drugs, in order to learn more about their function. We will use these techniques to characterize the changes seen in these pathways in PD, and determine if these changes can be normalized with drugs, thereby reducing motor symptoms in PD model mice.

Methods/Design: Both healthy mice and mice with PD symptoms will be genetically engineered to make neurons that respond to specific wavelengths of light (blue and yellow). We plan to examine the thalamus brain pathways in both PD mice and healthy mice to see if there are differences between them. By activating specific brain cells with light and measuring how they communicate to the striatum, we can determine if changes in these pathways occur as a result of PD. We will then measure motor symptoms in PD mice before and after normalizing drugs are administered by conducting several behavioral tests.

Relevance to Diagnosis/Treatment of Parkinson’s disease: Most symptomatic treatments for PD motor symptoms rely on replacing dopamine. While this has been successful, it is not without some serious and debilitating side effects. The thalamis brain pathway being tested in this study relies on a different neurotransmitter, glutamate. If the imbalance in brain pathways that lead to PD symptoms can be corrected by using glutamate instead of dopamine, this opens up the possibilities for new PD therapeutics.

September 2017 Project Update:

Our ongoing studies reveal that, in a mouse model of Parkinson’s disease, the brain circuitry connecting the thalamus and the striatum is unexpectedly altered in a way that could contribute to motor symptoms of PD. In the brain, there are two major interacting circuits that control movement that are affected by PD. It is widely thought that changes to these brain circuits is solely a consequence of the loss of the ability to respond to dopamine. Our studies refute that hypothesis and show that there is an alteration in activity of neurons from the thalamus that sends signals to the striatum. The target of these thalamic neurons are cholinergic brain cells that have long been known to play a role in PD. We found that when the thalamic brain cells become more active they, in turn, activate the cholinergic neurons and lead to an increase in PD symptoms. By suppressing these activity of these specific thalamic neurons we alleviated the difficulty PD mice had in moving, suggesting it contributes in an important way to symptoms in PD patients. Our research to identify the changes in this circuitry and its molecular underpinnings could create new targets for symptomatic therapy.